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HER-2 breast cancer may benefit from lapatinib/trastuzumab combination therapy

Baselga J. Lancet. 2012;doi:10.1016/S0140-6736(11)61847-3.

Issue: February 25, 2012

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Combination therapy with lapatinib and trastuzumab was linked to higher pathological complete response rates than either of the drugs administered individually, according to study results.

Researchers from the NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) study aimed to determine whether the combination of lapatinib (Tykerb, GlaxoSmithKline) and trastuzumab (Herceptin, Genentech) is more effective than single-agent therapy in models of HER-2–overexpressing breast cancer. They suggested that the two drugs have complementary mechanisms of action and synergistic antitumor activity.
The trial — which involved 455 patients from 23 countries — was conducted from Jan. 5, 2008, to May 27, 2010. Eligible participants had HER-2–positive tumors larger than 2 cm in diameter.

There were three arms of the study: 154 patients were assigned 1,500 mg oral lapatinib; 149 patients were assigned a trastuzumab regimen that involved a loading dose of 4 mg/m2 and subsequent doses of 2 mg/kg; and 152 patients were assigned combination therapy of 1,000 mg lapatinib plus the trastuzumab regimen.

The first 6 weeks of treatment involved only anti-HER-2 therapies. After 6 weeks, a weekly 80 mg/m2 dose of paclitaxel was administered for 12 weeks before surgery. After surgery, adjuvant chemotherapy was followed by targeted therapy as in the neoadjuvant phase. This regimen was administered for 52 weeks. The primary endpoint of pathological complete response rate was evaluated by intention-to-treat analysis.

A significantly higher pathological complete response rate was observed in the combination group (51.3%; 95% CI, 43.1-59.5) than in the trastuzumab-alone group (29.5%; 95% CI, 22.4-37.5), resulting in a difference of 21.1% (95% CI, 9.1-34.2).

The pathological complete response rate in the lapatinib-alone group was 24.7% (95% CI, 18.1-32.3), which the researchers said was not significantly different from the rate in the trastuzumab-alone group (difference of −4.8%; 95% CI, −17.6 to 8.2).

There were no reported cardiac dysfunctions. Grade-3 diarrhea occurred more frequently in the lapatinib-alone (23.4%) and lapatinib-plus-trastuzumab (21.1%) groups than in the trastuzumab group (2%).

The rate of grade-3 liver-enzyme alterations was 17.5% in the lapatinib group, 9.9% in the lapatinib plus trastuzumab group, and 7.4% in the trastuzumab group.

“Dual inhibition of HER-2 might be a valid approach to treatment of HER-2–positive breast cancer in the neoadjuvant setting,” the researchers wrote.

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